The main research objective of this proposal is to improve the use of Wolbachia as a biocontrol of vector-borne disease. Wolbachia are maternally transmitted bacteria that reside in the cells of arthropod hosts. Wolbachia reproductively manipulate their hosts using a variety of mechanisms including cytoplasmic incompatibility, which reduces the number of offspring produced when uninfected females mate with infected males. Dr. Turelli (sponsor) and other members of the Eliminate Dengue Team (://www.eliminatedengue.com/) are using Wolbachia from Drosophila flies to reduce the transmission of the dengue virus from Aedes mosquitoes to humans. Successful establishment of Wolbachia-Aedes associations in nature has the potential to reduce the occurrence of dengue fever in the 2.5 billion people currently at risk of infection. However, this requires the identification of contexts that enable the spread of Wolbachia infections through host populations. By identifying the ecological and genetic contexts that facilitate the spread of Wolbachia infections, and the genetic factors underlying important phenotypes, the applicant's research will fundamentally improve the use of Wolbachia as a biocontrol of vector-borne disease. AIM 1 will identify the ecological and genetic contexts that facilitate the spread and maintenance of Wolbachia infections in host populations. Using genomics, microscopy, and fitness assays, this aim will then evaluate how tripartite genomic interactions functionally impact the strength of reproductive alterations inflicted upon hosts by Wolbachia. AIM 2 will then evaluate the phylogeographic history of Wolbachia infections, and the capacity for rapid coevolution of Wolbachia-host associations. Determining the capacity for rapid coevolution is critical considering that theory predicts that coevolution of Wolbachia-host associations towards mutualism should enable the proliferation of Wolbachia through host populations. The applicant will receive training in cell biology, microscopy, genetics, genomics, and in new systems (i.e., Drosophila suzukii and Aedes aegypti). The sponsor, his collaborators, and the faculty at UC Davis are particularly capable to assist the applicant in achieving his goals. The applicant will build a direct and long-term collaboration with the Eliminate Dengue Team enabling him to work with those on the vanguard of applying Wolbachia as a biocontrol of vector-borne diseases throughout his career as a principal investigator.